Cytokines are active in cell proliferation and differentiation and affect such activities as leukocyte migration and function, hematopoietic cell numbers, temperature regulation, acute response to infections, tissue remodeling and cell survival. Since cytokines are produced in groups and in patterns characteristic of the particular stimulus or disease, studies using antibodies or other drugs that modify the activity of a particular cytokine are beginning to elucidate the roles of individual cytokines in pathology and physiology. For purposes of example, two cytokines which are rapidly expressed in response to fibroblast growth factor (FGF) and inflammatory response (AIF-1), respectively, will be described.
FIN 14 is an inducible gene which was expressed in cells transfected with a genomic fragment of the FGF-4, a growth factor known to play a crucial role in mouse and Xenopus embryonic growth and development (Feldman, B et al. (1995) Science 267:246-9; Amaya, E. et al. (1991) Cell 66:257-70). The transcript for FIN 14 was originally isolated using subtractive hybridization between the transformed 15 cell line and untransfomed mouse NIH3T3 cells, the line from which A15 was derived. FIN 14 is maximally induced 12-18 hours after FGF-4 treatment and is considered to be a delayed or late response transcript when compared to intermediate-early response genes such as transcription factors. Further studies showed that FIN 14 maps to the distal arm of mouse chromosome 6 and is also expressed in response to mitogenic stimulation (serum; Guthridge, M. A. (1996) Oncogene 12:1267-78).
AIF-1, allograft inflammatory factor-1, was first cloned and characterized from rat cardiac allografts. AIF-1 is a 17 kD hydrophillic protein which is selectively expressed in macrophages and neutrophils, and when stimulated by T-cell interferon-gamma, AIF-1 expression increases six-fold. AIF-1 transcripts are lacking in cardiac syngrafts and in host hearts, and transcript levels can be reduced in allografts by introducing CTLA-4 immunoglobulin (Utans, U. et al. (1995) J. Clin. Invest. 95:2954-62).
AIF-1 has 77% overall amino acid identity with IBA1; however, most of the variability is in the first 9 and in the last 20 residues. Both of these molecules share a calcium binding domain, D.sub.58 LNGNGDIDIMSL.sub.70. Imai, Y et al. (Biochem. Biophys. Res. Comm. 224:855-862) report that IBA1 is highly expressed in spleen, testes, and microglia where the protein may mediate calcium signaling.
The discovery of novel cytokines and the molecules encoding them provides a means to investigate cell proliferation, leukocyte migration and function, response to infections and tissue remodeling under normal and disease conditions. Such novel cytokines satisfy a need in the art by providing new compositions useful in diagnosing and treating cancers, inflammation, allograft rejection, neurodegenerative diseases, and conditions affecting pregnancy, growth and development